1022
S.L. Feng et al. / Chinese Chemical Letters 22 (2011) 1021–1024
Table 1
a
Condition screening for Rh-catalyzed N-benzylation of benzenesulfonamide with benzyl alcohol .
[TD$INLE]
RhCl(PPh ) (x mol%)
3
3
Ph
OH + PhSO NH2
Ph
NHSO Ph
3aa
Ph
+ H O
2
2
2
NSO Ph
2
base (y equiv.)
atm., T, t
1
a
2a
4aa
.
b
b
Entry
x
Base (y)
atm., T, t
3aa yield (%)
3aa/4aa
1
5
5
5
5
–
5
5
5
5
2
2
1
2
2
2
2
K
K
K
K
K
–
2
2
2
2
2
CO
CO
CO
CO
CO
3
3
3
3
3
(1.0)
(1.0)
(1.0)
(1.0)
(1.0)
N
N
N
2
2
2
, 100–120 8C, 8 h
, 120 8C, 8 h
, 120 8C, 24 h
–
–
c
2
–
–
d
3
67
>99/1
>99/1
–
4
5
Air, 120 8C, 24 h
Air, 120 8C, 24 h
Air, 120 8C, 12 h
Air, 120 8C, 24 h
Air, 120 8C, 24 h
Air, 120 8C, 24 h
Air, 120 8C, 12 h
Air, 120 8C, 12 h
Air, 120 8C, 24 h
Air, 150 8C, 24 h
Air, 100 8C, 24 h
Air, 120 8C, 24 h
Air, 120 8C, 24 h
96 (>99)
–
e
6
–
1/99
7
8
Na
Cs
2
CO
3
(1.0)
(1.0)
(47)
61/39
>99/1
>99/1
–
2
CO
PO
CO
3
90 (>99)
83 (>99)
Trace
95 (>99)
85 (>99)
94
9
K
K
K
K
K
K
K
K
3
2
2
2
2
2
2
2
4
(1.0)
(1.0)
(1.0)
(1.0)
(1.0)
(1.0)
(0.5)
(0.1)
c
1
1
1
1
1
1
1
0
1
2
3
4
5
6
3
3
3
3
3
3
3
CO
CO
CO
CO
CO
CO
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
88
61
26
a
Unless otherwise noted, 2a (1 mmol), base, and RhCl(PPh
3
)
3
in 1a (6 mmol, 6 equiv.) were heated in a sealed Schlenk tube. The mixture was then
used newly distilled and degassed 1a and solvents.
Isolated yields based on 2a. Yields in parenthesis are referred to GC yields. Ratios of 3aa/4aa were determined by GC–MS analysis.
monitored by TLC and/or GC–MS. Unless otherwise noted, reactions under N
b
2
c
d
e
1
a (2 mmol, 2 equiv.) and 2a (1 mmol) in 0.5 mL solvents (DMF, dioxane, THF, toluene, etc.) in a Schlenk tube.
Commercial 1a without further treatment was directly added under N without degassed.
aa was detected in 40% yield by GC.
2
4
even using solvents to promote the reaction (entry 2). However, when commercial 1a was accidentally added without
degassed, the reaction surprisingly gave 67% isolated yield of N-benzylbenzenesulfonamide 3aa (entry 3). Thus
inspired, another reaction, directly heated under air using substrates without further treatment and purification,
afforded almost quantitative yield of the product (entry 4). Under present condition, yield of the byproduct, N-
benzylidenebenzenesulfonamide 4aa, was usually very low. Thus, the product could be isolated in high selectivity
(
entries 3–4). Further condition screening showed that RhCl(PPh ) and base are both essential. Without Rh catalyst,
3 3
no reaction occurred at all (entry 5). Without base, large amount of byproduct 4aa was detected (entry 6). Similar to
recent reports [15,16], 4aa was possibly formed due to the oxidation by the oxygen in air. Besides, preliminary base
(
be reduced not to affect the reaction greatly (entries 11–12). Thus, with 2 mol% RhCl (PPh ) , 3aa could still be
entries 7–9) and solvent screenings (entry 10) showed that K CO and alcohol 1a are the best. Catalyst loading could
2 3
3
3
isolated in 95% yield in 12 h (entry 11). Lower catalyst loading (1 mol%) resulted in a slight decrease (entry 12). It
seems higher temperature heating is unnecessary (entry 13), but lower temperature could result in decreased product
yield (entry 14). Reduced base loadings also resulted in decreased product yield (entries 15–16).
This Rh-catalyzed aerobic N-alkylation protocol was then extended to other substrates (Table 2), showing that this
aerobic method is potentially general. Thus, arenesulfonamides (entries 1–17) reacted with benzylic alcohols (entries
1
–15) efficiently to give good to high yields of the desired N-alkylated sulfonamides. Other alcohols (entries 16–17),
an amide and an amine (entries 18–19) also worked well under similar albeit not optimized conditions. Thus, 2-
thiophenylmethyl alcohol and cinnamic alcohol reacted similarly to give good product yields (entries 16–17). The
reaction of benzamide is more difficult and had to be heated to 180 8C (entry 18). While the reaction of 2-pyridyl
amine showed that amines could also react similarly to give the N-alkylation product smoothly (entry 19).
Although mechanistic aspects of above Rh-catalyzed aerobic N-alkylation reactions are still not exactly clear at
present, it should be interesting that it is possibly different to the documented mechanisms [7–10], since the present
reactions cannot proceed under anaerobic conditions as the conventional reactions did but have to be performed under
air. Most probably, these aerobic reactions take place via Rh-catalyzed aerobic alcohol oxidation to aldehydes [17,18]